FoxO transcription factors (FoxO1, FoxO3a, FoxO4, FoxO6) are a highly evolutionary conserved subfamily of the 'forkhead' box proteins. They have traditionally been considered tumor suppressors, but FoxO1 also exhibits oncogenic properties. The complex nature of FoxO1 is illustrated by its various roles in B cell development and differentiation, immunoglobulin gene rearrangement and cell-surface B cell receptor (BCR) structure, DNA damage control, cell cycle regulation, and germinal center reaction. FoxO1 is tightly regulated at a transcriptional (STAT3, HEB, EBF, FoxOs) and post-transcriptional level (Akt, AMPK, CDK2, GSK3, IKKs, JNK, MAPK/Erk, SGK1, miRNA). In B cell malignancies, recurrent FoxO1 activating mutations (S22/T24) and aberrant nuclear export and activity have been described, underscoring the potential of its therapeutic inhibition. Here, we review FoxO1's roles across B cell and myeloid malignancies, namely acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), follicular lymphoma (FL), diffuse large B cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Burkitt lymphoma (BL), Hodgkin lymphoma (HL), and multiple myeloma (MM). We also discuss preclinical evidence for FoxO1 targeting by currently available inhibitors (AS1708727, AS1842856, cpd10).

Central European Institute of Technology Masaryk University Brno Czech Republic

Department of Internal Medicine Hematology and Oncology University Hospital Brno and Faculty of Medicine Brno Czech Republic

Zobrazit více v PubMed

Paik J‐H, Kollipara R, Chu G, Ji H, Xiao Y, Ding Z, Miao L, Tothova Z, Horner JW, Carrasco DR PubMed PMC

Dengler HS, Baracho GV, Omori SA, Bruckner S, Arden K, Castrillon DH, DePinho RA and Rickert RC (2008) Distinct roles for Foxo1 at multiple stages of B cell differentiation. Nat Immunol 9, 1388–1398. PubMed PMC

Srinivasan L, Sasaki Y, Calado DP, Zhang B, Paik JH, DePinho RA, Kutok JL, Kearney JF, Otipoby KL and Rajewsky K (2009) PI3 kinase signals BCR‐dependent mature B cell survival. Cell 139, 573–586. PubMed PMC

Dominguez‐Sola D, Kung J, Holmes AB, Wells VA, Mo T, Basso K and Dalla‐Favera R (2015) The FOXO1 transcription factor instructs the germinal center dark zone program. Immunity 43, 1064–1074. PubMed

Sander S, Chu VT, Yasuda T, Franklin A, Graf R, Calado DP, Li S, Imami K, Selbach M, Di Virgilio M PubMed

Xie L, Ushmorov A, Leithäuser F, Guan H, Steidl C, Färbinger J, Pelzer C, Vogel MJ, Maier HJ, Gascoyne RD PubMed

Bloedjes TA, De Wilde G, Maas C, Eldering E, Bende RJ, Van Noesel CJM, Pals ST, Spaargaren M and Guikema JEJ (2020) AKT signaling restrains tumor suppressive functions of FOXO transcription factors and GSK3 kinase in multiple myeloma. Blood Adv 4, 4151–4164. PubMed PMC

Zhou P, Blain AE, Newman AM, Zaka M, Chagaluka G, Adlar FR, Offor UT, Broadbent C, Chaytor L, Whitehead A PubMed PMC

Jang J‐Y, Hwang I, Pan H, Yao J, Alinari L, Imada E, Zanettini C, Kluk MJ, Wang Y, Lee Y PubMed PMC

Ondrisova L, Seda V, Hlavac K, Pavelkova P, Hoferkova E, Chiodin G, Kostalova L, Mladonicka Pavlasova G, Filip D, Vecera J PubMed DOI PMC

Trinh DL, Scott DW, Morin RD, Mendez‐Lago M, An J, Jones SJM, Mungall AJ, Zhao Y, Schein J, Steidl C PubMed PMC

Nagashima T, Shigematsu N, Maruki R, Urano Y, Tanaka H, Shimaya A, Shimokawa T and Shibasaki M (2010) Discovery of novel Forkhead box O1 inhibitors for treating type 2 diabetes: improvement of fasting Glycemia in diabetic PubMed

Tanaka H, Nagashima T, Shimaya A, Urano Y, Shimokawa T and Shibasaki M (2010) Effects of the novel Foxo1 inhibitor AS1708727 on plasma glucose and triglyceride levels in diabetic db/db mice. Eur J Pharmacol 645, 185–191. PubMed

Brent MM, Anand R and Marmorstein R (2008) Structural basis for DNA recognition by FoxO1 and its regulation by posttranslational modification. Structure 16, 1407–1416. PubMed PMC

Psenakova K, Kohoutova K, Obsilova V, Ausserlechner MJ, Veverka V and Obsil T (2019) Forkhead domains of FOXO transcription factors differ in both overall conformation and dynamics. Cells 8, E966. PubMed PMC

Hatta M and Cirillo LA (2007) Chromatin opening and stable perturbation of core histone:DNA contacts by FoxO1. J Biol Chem 282, 35583–35593. PubMed

Wang F, Marshall CB, Yamamoto K, Li G‐Y, Plevin MJ, You H, Mak TW and Ikura M (2008) Biochemical and structural characterization of an intramolecular interaction in FOXO3a and its binding with p53. J Mol Biol 384, 590–603. PubMed

Obsil T and Obsilova V (2008) Structure/function relationships underlying regulation of FOXO transcription factors. Oncogene 27, 2263–2275. PubMed

Jacobs FMJ, van der Heide LP, Wijchers PJEC, Burbach JPH, Hoekman MFM and Smidt MP (2003) FoxO6, a novel member of the FoxO class of transcription factors with distinct shuttling dynamics. J Biol Chem 278, 35959–35967. PubMed

Lees J, Hay J, Moles MW and Michie AM (2023) The discrete roles of individual FOXO transcription factor family members in B‐cell malignancies. Front Immunol 14, 1179101. PubMed PMC

Oh H‐M, Yu C‐R, Golestaneh N, Amadi‐Obi A, Lee YS, Eseonu A, Mahdi RM and Egwuagu CE (2011) STAT3 protein promotes T‐cell survival and inhibits interleukin‐2 production through up‐regulation of class O Forkhead transcription factors. J Biol Chem 286, 30888–30897. PubMed PMC

Welinder E, Mansson R, Mercer EM, Bryder D, Sigvardsson M and Murre C (2011) The transcription factors E2A and HEB act in concert to induce the expression of FOXO1 in the common lymphoid progenitor. Proc Natl Acad Sci U S A 108, 17402–17407. PubMed PMC

Essaghir A, Dif N, Marbehant CY, Coffer PJ and Demoulin J‐B (2009) The transcription of FOXO genes is stimulated by FOXO3 and repressed by growth factors. J Biol Chem 284, 10334–10342. PubMed PMC

Gaudette BT, Dwivedi B, Chitta KS, Poulain S, Powell D, Vertino P, Leleu X, Lonial S, Chanan‐Khan AA, Kowalski J PubMed PMC

Osswald CD, Xie L, Guan H, Herrmann F, Pick SM, Vogel MJ, Gehringer F, Chan FC, Steidl C, Wirth T PubMed PMC

Dobson M, Ramakrishnan G, Ma S, Kaplun L, Balan V, Fridman R and Tzivion G (2011) Bimodal regulation of FoxO3 by AKT and 14‐3‐3. Biochim Biophys Acta 1813, 1453–1464. PubMed PMC

Ushmorov A and Wirth T (2018) FOXO in B‐cell lymphopoiesis and B cell neoplasia. Semin Cancer Biol 50, 132–141. PubMed

Brownawell AM, Kops GJ, Macara IG and Burgering BM (2001) Inhibition of nuclear import by protein kinase B (Akt) regulates the subcellular distribution and activity of the forkhead transcription factor AFX. Mol Cell Biol 21, 3534–3546. PubMed PMC

Brunet A, Bonni A, Zigmond MJ, Lin MZ, Juo P, Hu LS, Anderson MJ, Arden KC, Blenis J and Greenberg ME (1999) Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell 96, 857–868. PubMed

Guo S, Rena G, Cichy S, He X, Cohen P and Unterman T (1999) Phosphorylation of serine 256 by protein kinase B disrupts transactivation by FKHR and mediates effects of insulin on insulin‐like growth factor‐binding protein‐1 promoter activity through a conserved insulin response sequence. J Biol Chem 274, 17184–17192. PubMed

Nielsen MD, Luo X, Biteau B, Syverson K and Jasper H (2008) 14‐3‐3ε antagonizes FoxO to control growth, apoptosis and longevity in drosophila. Aging Cell 7, 688–699. PubMed PMC

Obsilova V, Vecer J, Herman P, Pabianova A, Sulc M, Teisinger J, Boura E and Obsil T (2005) 14‐3‐3 protein interacts with nuclear localization sequence of Forkhead transcription factor FoxO4. Biochemistry 44, 11608–11617. PubMed

Silhan J, Vacha P, Strnadova P, Vecer J, Herman P, Sulc M, Teisinger J, Obsilova V and Obsil T (2009) 14‐3‐3 protein masks the DNA binding interface of forkhead transcription factor FOXO4. J Biol Chem 284, 19349–19360. PubMed PMC

Christensen R, de la Torre‐Ubieta L, Bonni A and Colón‐Ramos DA (2011) A conserved PTEN/FOXO pathway regulates neuronal morphology during PubMed PMC

Yan L, Lavin VA, Moser LR, Cui Q, Kanies C and Yang E (2008) PP2A regulates the pro‐apoptotic activity of FOXO1. J Biol Chem 283, 7411–7420. PubMed PMC

Brenkman AB, de Keizer PLJ, van den Broek NJF, Jochemsen AG and Burgering BMT (2008) Mdm2 induces mono‐ubiquitination of FOXO4. PLoS One 3, e2819. PubMed PMC

Matsuzaki H, Daitoku H, Hatta M, Aoyama H, Yoshimochi K and Fukamizu A (2005) Acetylation of Foxo1 alters its DNA‐binding ability and sensitivity to phosphorylation. Proc Natl Acad Sci U S A 102, 11278–11283. PubMed PMC

Yamagata K, Daitoku H, Takahashi Y, Namiki K, Hisatake K, Kako K, Mukai H, Kasuya Y and Fukamizu A (2008) Arginine methylation of FOXO transcription factors inhibits their phosphorylation by Akt. Mol Cell 32, 221–231. PubMed

Ramaswamy S, Nakamura N, Sansal I, Bergeron L and Sellers WR (2002) A novel mechanism of gene regulation and tumor suppression by the transcription factor FKHR. Cancer Cell 2, 81–91. PubMed

Schmidt M, Fernandez de Mattos S, van der Horst A, Klompmaker R, Kops GJPL, Lam EW‐F, Burgering BMT and Medema RH (2002) Cell cycle inhibition by FoxO forkhead transcription factors involves downregulation of cyclin D. Mol Cell Biol 22, 7842–7852. PubMed PMC

Nakamura N, Ramaswamy S, Vazquez F, Signoretti S, Loda M and Sellers WR (2000) Forkhead transcription factors are critical effectors of cell death and cell cycle arrest downstream of PTEN. Mol Cell Biol 20, 8969–8982. PubMed PMC

Tran H, Brunet A, Grenier JM, Datta SR, Fornace AJ, DiStefano PS, Chiang LW and Greenberg ME (2002) DNA repair pathway stimulated by the forkhead transcription factor FOXO3a through the Gadd45 protein. Science 296, 530–534. PubMed

Yalcin S, Zhang X, Luciano JP, Mungamuri SK, Marinkovic D, Vercherat C, Sarkar A, Grisotto M, Taneja R and Ghaffari S (2008) Foxo3 is essential for the regulation of ataxia telangiectasia mutated and oxidative stress‐mediated homeostasis of hematopoietic stem cells. J Biol Chem 283, 25692–25705. PubMed

Kops GJPL, Dansen TB, Polderman PE, Saarloos I, Wirtz KWA, Coffer PJ, Huang T‐T, Bos JL, Medema RH and Burgering BMT (2002) Forkhead transcription factor FOXO3a protects quiescent cells from oxidative stress. Nature 419, 316–321. PubMed

Modur V, Nagarajan R, Evers BM and Milbrandt J (2002) FOXO proteins regulate tumor necrosis factor‐related apoptosis inducing ligand expression. Implications for PTEN mutation in prostate cancer. J Biol Chem 277, 47928–47937. PubMed

Stahl M, Dijkers PF, Kops GJPL, Lens SMA, Coffer PJ, Burgering BMT and Medema RH (2002) The Forkhead transcription factor FoxO regulates transcription of p27 PubMed

You H, Pellegrini M, Tsuchihara K, Yamamoto K, Hacker G, Erlacher M, Villunger A and Mak TW (2006) FOXO3a‐dependent regulation of Puma in response to cytokine/growth factor withdrawal. J Exp Med 203, 1657–1663. PubMed PMC

Huang H, Regan KM, Lou Z, Chen J and Tindall DJ (2006) CDK2‐dependent phosphorylation of FOXO1 as an apoptotic response to DNA damage. Science 314, 294–297. PubMed

Rena G, Guo S, Cichy SC, Unterman TG and Cohen P (1999) Phosphorylation of the transcription factor Forkhead family member FKHR by protein kinase B. J Biol Chem 274, 17179–17183. PubMed

Bashir T, Dorrello NV, Amador V, Guardavaccaro D and Pagano M (2004) Control of the SCF(Skp2‐Cks1) ubiquitin ligase by the APC/C(Cdh1) ubiquitin ligase. Nature 428, 190–193. PubMed

Wei W, Ayad NG, Wan Y, Zhang G‐J, Kirschner MW and Kaelin WG (2004) Degradation of the SCF component Skp2 in cell‐cycle phase G1 by the anaphase‐promoting complex. Nature 428, 194–198. PubMed

Liu P, Kao TP and Huang H (2008) CDK1 promotes cell proliferation and survival via phosphorylation and inhibition of FOXO1 transcription factor. Oncogene 27, 4733–4744. PubMed

Cheng M, Nie Y, Song M, Chen F and Yu Y (2024) Forkhead box O proteins: steering the course of stem cell fate. Cell Regen 13, 7. PubMed PMC

Renault VM, Rafalski VA, Morgan AA, Salih DAM, Brett JO, Webb AE, Villeda SA, Thekkat PU, Guillerey C, Denko NC PubMed PMC

García‐Prat L, Perdiguero E, Alonso‐Martín S, Dell'Orso S, Ravichandran S, Brooks SR, Juan AH, Campanario S, Jiang K, Hong X PubMed

Webb AE, Pollina EA, Vierbuchen T, Urbán N, Ucar D, Leeman DS, Martynoga B, Sewak M, Rando TA, Guillemot F PubMed PMC

Audesse AJ, Dhakal S, Hassell L‐A, Gardell Z, Nemtsova Y and Webb AE (2019) FOXO3 directly regulates an autophagy network to functionally regulate proteostasis in adult neural stem cells. PLoS Genet 15, e1008097. PubMed PMC

Warr MR, Binnewies M, Flach J, Reynaud D, Garg T, Malhotra R, Debnath J and Passegué E (2013) FOXO3A directs a protective autophagy program in haematopoietic stem cells. Nature 494, 323–327. PubMed PMC

Zhang X, Yalcin S, Lee D‐F, Yeh T‐YJ, Lee S‐M, Su J, Mungamuri SK, Rimmelé P, Kennedy M, Sellers R PubMed PMC

Liu P, Liu K, Gu H, Wang W, Gong J, Zhu Y, Zhao Q, Cao J, Han C, Gao F PubMed PMC

Vilchez D, Boyer L, Morantte I, Lutz M, Merkwirth C, Joyce D, Spencer B, Page L, Masliah E, Berggren WT PubMed PMC

Bakker WJ, Blázquez‐Domingo M, Kolbus A, Besooyen J, Steinlein P, Beug H, Coffer PJ, Löwenberg B, Von Lindern M and Van Dijk TB (2004) FoxO3a regulates erythroid differentiation and induces BTG1, an activator of protein arginine methyl transferase 1. J Cell Biol 164, 175–184. PubMed PMC

Teixeira CC, Liu Y, Thant LM, Pang J, Palmer G and Alikhani M (2010) Foxo1, a novel regulator of osteoblast differentiation and Skeletogenesis. J Biol Chem 285, 31055–31065. PubMed PMC

Iyer S, Ambrogini E, Bartell SM, Han L, Roberson PK, De Cabo R, Jilka RL, Weinstein RS, O'Brien CA, Manolagas SC PubMed PMC

Higuchi M, Dusting GJ, Peshavariya H, Jiang F, Hsiao ST‐F, Chan EC and Liu G‐S (2013) Differentiation of human adipose‐derived stem cells into fat involves reactive oxygen species and Forkhead box O1 mediated upregulation of antioxidant enzymes. Stem Cells Dev 22, 878–888. PubMed PMC

Kurakazu I, Akasaki Y, Hayashida M, Tsushima H, Goto N, Sueishi T, Toya M, Kuwahara M, Okazaki K, Duffy T PubMed PMC

Yuan S, Zhang L, Ji L, Zhong S, Jiang L, Wan Y, Song Y, Zhang C and Wang R (2022) FoxO3a cooperates with RUNX1 to promote chondrogenesis and terminal hypertrophic of the chondrogenic progenitor cells. Biochem Biophys Res Commun 589, 41–47. PubMed

Miyamoto K, Miyamoto T, Kato R, Yoshimura A, Motoyama N and Suda T (2008) FoxO3a regulates hematopoietic homeostasis through a negative feedback pathway in conditions of stress or aging. Blood 112, 4485–4493. PubMed PMC

Tsai W‐B, Chung YM, Takahashi Y, Xu Z and Hu MC‐T (2008) Functional interaction between FOXO3a and ATM regulates DNA damage response. Nat Cell Biol 10, 460–467. PubMed PMC

Peña‐Pérez L, Kharazi S, Frengen N, Krstic A, Bouderlique T, Hauenstein J, He M, Somuncular E, Li Wang X, Dahlberg C PubMed PMC

Kuo TC and Schlissel MS (2009) Mechanisms controlling expression of the RAG locus during lymphocyte development. Curr Opin Immunol 21, 173–178. PubMed PMC

Amin RH and Schlissel MS (2008) Foxo1 directly regulates the transcription of recombination‐activating genes during B cell development. Nat Immunol 9, 613–622. PubMed PMC

Lam K‐P, Kühn R and Rajewsky K (1997) In vivo ablation of surface immunoglobulin on mature B cells by inducible gene targeting results in rapid cell death. Cell 90, 1073–1083. PubMed

Lee K, Heffington L, Jellusova J, Nam KT, Raybuck A, Cho SH, Thomas JW, Rickert RC and Boothby M (2013) Requirement for Rictor in homeostasis and function of mature B lymphoid cells. Blood 122, 2369–2379. PubMed PMC

Yusuf I, Zhu X, Kharas MG, Chen J and Fruman DA (2004) Optimal B‐cell proliferation requires phosphoinositide 3‐kinase‐dependent inactivation of FOXO transcription factors. Blood 104, 784–787. PubMed

Calamito M, Juntilla MM, Thomas M, Northrup DL, Rathmell J, Birnbaum MJ, Koretzky G and Allman D (2010) Akt1 and Akt2 promote peripheral B‐cell maturation and survival. Blood 115, 4043–4050. PubMed PMC

Chen J, Limon JJ, Blanc C, Peng SL and Fruman DA (2010) Foxo1 regulates marginal zone B‐cell development. Eur J Immunol 40, 1890–1896. PubMed PMC

Suzuki A, Kaisho T, Ohishi M, Tsukio‐Yamaguchi M, Tsubata T, Koni PA, Sasaki T, Mak TW and Nakano T (2003) Critical roles of Pten in B cell homeostasis and immunoglobulin class switch recombination. J Exp Med 197, 657–667. PubMed PMC

Cox E‐M, El‐Behi M, Ries S, Vogt JF, Kohlhaas V, Michna T, Manfroi B, Al‐Maarri M, Wanke F, Tirosh B PubMed

Setz CS, Khadour A, Renna V, Iype J, Gentner E, He X, Datta M, Young M, Nitschke L, Wienands J PubMed PMC

Inoue T, Shinnakasu R, Ise W, Kawai C, Egawa T and Kurosaki T (2017) The transcription factor Foxo1 controls germinal center B cell proliferation in response to T cell help. J Exp Med 214, 1181–1198. PubMed PMC

Oestreich KJ, Mohn SE and Weinmann AS (2012) Molecular mechanisms that control the expression and activity of Bcl‐6 in TH1 cells to regulate flexibility with a TFH‐like gene profile. Nat Immunol 13, 405–411. PubMed PMC

Park S‐R, Zan H, Pal Z, Zhang J, Al‐Qahtani A, Pone EJ, Xu Z, Mai T and Casali P (2009) HoxC4 binds to the promoter of the cytidine deaminase AID gene to induce AID expression, class‐switch DNA recombination and somatic hypermutation. Nat Immunol 10, 540–550. PubMed PMC

Omori SA, Cato MH, Anzelon‐Mills A, Puri KD, Shapiro‐Shelef M, Calame K and Rickert RC (2006) Regulation of class‐switch recombination and plasma cell differentiation by phosphatidylinositol 3‐kinase signaling. Immunity 25, 545–557. PubMed

Roberto MP, Varano G, Vinas‐Castells R, Holmes AB, Kumar R, Pasqualucci L, Farinha P, Scott DW and Dominguez‐Sola D (2021) Mutations in the transcription factor FOXO1 mimic positive selection signals to promote germinal center B cell expansion and lymphomagenesis. Immunity 54, 1807–1824.e14. PubMed PMC

Cornelis R, Hahne S, Taddeo A, Petkau G, Malko D, Durek P, Thiem M, Heiberger L, Peter L, Mohr E PubMed PMC

Vogel MJ, Xie L, Guan H, Tooze RM, Maier T, Kostezka U, Maier HJ, Holzmann K, Chan FC, Steidl C PubMed

Xie L, Ritz O, Leithäuser F, Guan H, Färbinger J, Weitzer CD, Gehringer F, Brüderlein S, Holzmann K, Vogel MJ PubMed PMC

Rizk M, Rizq O, Oshima M, Nakajima‐Takagi Y, Koide S, Saraya A, Isshiki Y, Chiba T, Yamazaki S, Ma A PubMed PMC

Corno C, Stucchi S, De Cesare M, Carenini N, Stamatakos S, Ciusani E, Minoli L, Scanziani E, Argueta C, Landesman Y PubMed

Wang J, Sun T, Meng Z, Wang L, Li M, Chen J, Qin T, Yu J, Zhang M, Bie Z PubMed

Uddin S, Hussain AR, Siraj AK, Manogaran PS, Al‐Jomah NA, Moorji A, Atizado V, Al‐Dayel F, Belgaumi A, El‐Solh H PubMed

Pfeifer M, Grau M, Lenze D, Wenzel S‐S, Wolf A, Wollert‐Wulf B, Dietze K, Nogai H, Storek B, Madle H PubMed PMC

Go H, Jang J‐Y, Kim P‐J, Kim Y‐G, Nam SJ, Paik JH, Kim TM, Heo DS, Kim C‐W and Jeon YK (2015) MicroRNA‐21 plays an oncogenic role by targeting FOXO1 and activating the PI3K/AKT pathway in diffuse large B‐cell lymphoma. Oncotarget 6, 15035–15049. PubMed PMC

Szydlowski M, Kiliszek P, Sewastianik T, Jablonska E, Bialopiotrowicz E, Gorniak P, Polak A, Markowicz S, Nowak E, Grygorowicz MA PubMed

Chen L, Monti S, Juszczynski P, Ouyang J, Chapuy B, Neuberg D, Doench JG, Bogusz AM, Habermann TM, Dogan A PubMed PMC

Sablon A, Bollaert E, Pirson C, Velghe AI and Demoulin J‐B (2022) FOXO1 forkhead domain mutants in B‐cell lymphoma lack transcriptional activity. Sci Rep 12, 1309. PubMed PMC

Layden HM, Ellis JD, Bomber ML, Bartlett LN, Hiebert SW and Stengel KR (2024) Mutant FOXO1 controls an oncogenic network via enhancer accessibility. Cell Genomics 4, 100537. PubMed PMC

Ning N, Zhang S, Wu Q, Li X, Kuang D, Duan Y, Xia M, Liu H, Weng J, Ba H PubMed PMC

Devan J, Janikova A and Mraz M (2018) New concepts in follicular lymphoma biology: from BCL2 to epigenetic regulators and non‐coding RNAs. Semin Oncol 45, 291–302. PubMed

Phan RT and Dalla‐Favera R (2004) The BCL6 proto‐oncogene suppresses p53 expression in germinal‐centre B cells. Nature 432, 635–639. PubMed

Pasqualucci L, Khiabanian H, Fangazio M, Vasishtha M, Messina M, Holmes AB, Ouillette P, Trifonov V, Rossi D, Tabbò F PubMed PMC

Pastore A, Jurinovic V, Kridel R, Hoster E, Staiger AM, Szczepanowski M, Pott C, Kopp N, Murakami M, Horn H PubMed

Bouska A, Zhang W, Gong Q, Iqbal J, Scuto A, Vose J, Ludvigsen M, Fu K, Weisenburger DD, Greiner TC PubMed PMC

Kabrani E, Chu VT, Tasouri E, Sommermann T, Baßler K, Ulas T, Zenz T, Bullinger L, Schultze JL, Rajewsky K PubMed

Gehringer F, Weissinger SE, Swier LJ, Möller P, Wirth T and Ushmorov A (2019) FOXO1 confers maintenance of the dark zone proliferation and survival program and can Be pharmacologically targeted in Burkitt lymphoma. Cancer 11, E1427. PubMed PMC

Cosimo E, Tarafdar A, Moles MW, Holroyd AK, Malik N, Catherwood MA, Hay J, Dunn KM, Macdonald AM, Guichard SM PubMed PMC

Seda V, Vojackova E, Ondrisova L, Kostalova L, Sharma S, Loja T, Mladonicka Pavlasova G, Zicha D, Kudlickova Peskova M, Krivanek J PubMed PMC

Sharma S, Pavlasova GM, Seda V, Cerna KA, Vojackova E, Filip D, Ondrisova L, Sandova V, Kostalova L, Zeni PF PubMed PMC

Pavlasova G, Borsky M, Svobodova V, Oppelt J, Cerna K, Novotna J, Seda V, Fojtova M, Fajkus J, Brychtova Y PubMed

Pavlasova G, Borsky M, Seda V, Cerna K, Osickova J, Doubek M, Mayer J, Calogero R, Trbusek M, Pospisilova S PubMed PMC

Scheffold A, Jebaraj BMC, Tausch E, Bloehdorn J, Ghia P, Yahiaoui A, Dolnik A, Blätte TJ, Bullinger L, Dheenadayalan RP PubMed PMC

Ochodnicka‐Mackovicova K, Bahjat M, Bloedjes TA, Maas C, De Bruin AM, Bende RJ, Van Noesel CJM and Guikema JEJ (2015) NF‐κB and AKT signaling prevent DNA damage in transformed pre‐B cells by suppressing RAG1/2 expression and activity. Blood 126, 1324–1335. PubMed PMC

Köhrer S, Havranek O, Seyfried F, Hurtz C, Coffey GP, Kim E, Ten Hacken E, Jäger U, Vanura K, O'Brien S PubMed PMC

Swaminathan S, Klemm L, Park E, Papaemmanuil E, Ford A, Kweon S‐M, Trageser D, Hasselfeld B, Henke N, Mooster J PubMed PMC

Shojaee S, Chan LN, Buchner M, Cazzaniga V, Cosgun KN, Geng H, Qiu YH, Von Minden MD, Ernst T, Hochhaus A PubMed PMC

Nakae J, Kitamura T, Silver DL and Accili D (2001) The forkhead transcription factor Foxo1 (Fkhr) confers insulin sensitivity onto glucose‐6‐phosphatase expression. J Clin Invest 108, 1359–1367. PubMed PMC

Jackson JG, Kreisberg JI, Koterba AP, Yee D and Brattain MG (2000) Phosphorylation and nuclear exclusion of the forkhead transcription factor FKHR after epidermal growth factor treatment in human breast cancer cells. Oncogene 19, 4574–4581. PubMed

Altomonte J, Richter A, Harbaran S, Suriawinata J, Nakae J, Thung SN, Meseck M, Accili D and Dong H (2003) Inhibition of Foxo1 function is associated with improved fasting glycemia in diabetic mice. Am J Physiol Endocrinol Metab 285, E718–E728. PubMed

Zhang W, Patil S, Chauhan B, Guo S, Powell DR, Le J, Klotsas A, Matika R, Xiao X, Franks R PubMed

Haeusler RA, Han S and Accili D (2010) Hepatic FoxO1 ablation exacerbates lipid abnormalities during hyperglycemia. J Biol Chem 285, 26861–26868. PubMed PMC

Haeusler RA, Hartil K, Vaitheesvaran B, Arrieta‐Cruz I, Knight CM, Cook JR, Kammoun HL, Febbraio MA, Gutierrez‐Juarez R, Kurland IJ PubMed PMC

Langlet F, Haeusler RA, Lindén D, Ericson E, Norris T, Johansson A, Cook JR, Aizawa K, Wang L, Buettner C PubMed PMC

Lin S, Ptasinska A, Chen X, Shrestha M, Assi SA, Chin PS, Imperato MR, Aronow BJ, Zhang J, Weirauch MT PubMed PMC

Santamaría CM, Chillón MC, García‐Sanz R, Pérez C, Caballero MD, Ramos F, De Coca AG, Alonso JM, Giraldo P, Bernal T PubMed

Sakoe Y, Sakoe K, Kirito K, Ozawa K and Komatsu N (2010) FOXO3A as a key molecule for all‐trans retinoic acid–induced granulocytic differentiation and apoptosis in acute promyelocytic leukemia. Blood 115, 3787–3795. PubMed

Sykes SM, Lane SW, Bullinger L, Kalaitzidis D, Yusuf R, Saez B, Ferraro F, Mercier F, Singh H, Brumme KM PubMed PMC

Kurayoshi K, Takase Y, Ueno M, Ohta K, Fuse K, Ikeda S, Watanabe T, Nishida Y, Horike S, Hosomichi K PubMed PMC

Wang F, Demir S, Gehringer F, Osswald CD, Seyfried F, Enzenmüller S, Eckhoff SM, Maier T, Holzmann K, Debatin K‐M PubMed

Bhansali RS, Rammohan M, Lee P, Laurent AP, Wen Q, Suraneni P, Yip BH, Tsai Y‐C, Jenni S, Bornhauser B PubMed PMC

Musilova K and Mraz M (2015) MicroRNAs in B‐cell lymphomas: how a complex biology gets more complex. Leukemia 29, 1004–1017. PubMed

Hoferkova E, Seda V, Kadakova S, Verner J, Loja T, Matulova K, Skuhrova Francova H, Ondrouskova E, Filip D, Blavet N PubMed PMC

Firat E and Niedermann G (2016) FoxO proteins or loss of functional p53 maintain stemness of glioblastoma stem cells and survival after ionizing radiation plus PI3K/mTOR inhibition. Oncotarget 7, 54883–54896. PubMed PMC

Martinez E, Vazquez N, Lopez A, Fanniel V, Sanchez L, Marks R, Hinojosa L, Cuello V, Cuevas M, Rodriguez A PubMed PMC

Flores D, Lopez A, Udawant S, Gunn B and Keniry M (2023) The foxo1 inhibitor as1842856 triggers apoptosis in glioblastoma multiforme and basal‐like breast cancer cells. FEBS Open Bio 13, 352–362. PubMed PMC

Lee Y‐K, Diaz B, Deroose M, Lee SX, Belvedere S, Accili D, Leibel RL and Lin HV (2021) FOXO1 inhibition synergizes with FGF21 to normalize glucose control in diabetic mice. Mol Metab 49, 101187. PubMed PMC

Bushweller JH (2019) Targeting transcription factors in cancer – from undruggable to reality. Nat Rev Cancer 19, 611–624. PubMed PMC

Furuyama T, Kitayama K, Yamashita H and Mori N (2003) Forkhead transcription factor FOXO1 (FKHR)‐dependent induction of PDK4 gene expression in skeletal muscle during energy deprivation. Biochem J 375, 365–371. PubMed PMC

Matsumoto M, Pocai A, Rossetti L, DePinho RA and Accili D (2007) Impaired regulation of hepatic glucose production in mice lacking the Forkhead transcription factor Foxo1 in liver. Cell Metab 6, 208–216. PubMed

Zhang T, Kim DH, Xiao X, Lee S, Gong Z, Muzumdar R, Calabuig‐Navarro V, Yamauchi J, Harashima H, Wang R PubMed PMC

Chen J, Lu Y, Tian M and Huang Q (2019) Molecular mechanisms of FOXO1 in adipocyte differentiation. J Mol Endocrinol 62, R239–R253. PubMed

Yu W, Chen C and Cheng J (2020) The role and molecular mechanism of FoxO1 in mediating cardiac hypertrophy. ESC Heart Fail 7, 3497–3504. PubMed PMC

Xu M, Chen X, Chen D, Yu B and Huang Z (2017) FoxO1: a novel insight into its molecular mechanisms in the regulation of skeletal muscle differentiation and fiber type specification. Oncotarget 8, 10662–10674. PubMed PMC

Teaney NA and Cyr NE (2023) FoxO1 as a tissue‐specific therapeutic target for type 2 diabetes. Front Endocrinol 14, 1286838. PubMed PMC

Glauser DA and Schlegel W (2007) The emerging role of FOXO transcription factors in pancreatic β cells. J Endocrinol 193, 195–207. PubMed

Talchai C and Accili D (2020) Methods for producing enteroendocrine cells that make and secrete insulin.

Kitamoto T, Lee Y‐K, Sultana N, Watanabe H, McKimpson WM, Du W, Fan J, Diaz B, Lin HV, Leibel RL PubMed PMC

Belvedere S, Lin HV, DeVita RJ, Turcotte S and Johnstone S (2023) Agents for the treatment of diseases by inhibition of foxo1.

Pavlasova G and Mraz M (2020) The regulation and function of CD20: an “enigma” of B‐cell biology and targeted therapy. Haematologica 105, 1494–1506. PubMed PMC

Pyrzynska B, Dwojak M, Zerrouqi A, Morlino G, Zapala P, Miazek N, Zagozdzon A, Bojarczuk K, Bobrowicz M, Siernicka M PubMed PMC

Morin RD, Assouline S, Alcaide M, Mohajeri A, Johnston RL, Chong L, Grewal J, Yu S, Fornika D, Bushell K PubMed

Blank CU, Haining WN, Held W, Hogan PG, Kallies A, Lugli E, Lynn RC, Philip M, Rao A, Restifo NP PubMed PMC

Weber EW, Maus MV and Mackall CL (2020) The emerging landscape of immune cell therapies. Cell 181, 46–62. PubMed PMC

Chan JD, Scheffler CM, Munoz I, Sek K, Lee JN, Huang Y‐K, Yap KM, Saw NYL, Li J, Chen AXY PubMed PMC

Doan AE, Mueller KP, Chen AY, Rouin GT, Chen Y, Daniel B, Lattin J, Markovska M, Mozarsky B, Arias‐Umana J PubMed PMC

Ma MCJ, Tadros S, Bouska A, Heavican T, Yang H, Deng Q, Moore D, Akhter A, Hartert K, Jain N PubMed PMC

Reddy A, Zhang J, Davis NS, Moffitt AB, Love CL, Waldrop A, Leppa S, Pasanen A, Meriranta L, Karjalainen‐Lindsberg M‐L PubMed PMC

FoxO1/Rictor axis induces a nongenetic adaptation to ibrutinib via Akt activation in chronic lymphocytic leukemia